The ultimate goal of our research is to develop an understanding of the response of cancer and viral infections to therapy using measurements of cellular DNA synthesis and positron emission tomography (PET) imaging. In order to make meaningful measurements of cellular proliferation using PET we are developing appropriate labeled nucleosides and producing detailed biochemical and kinetic models of their metabolism. Our ongoing studies have developed the techniques needed to obtain PET images with [C- 11] thymidine (TdR), which is incorporated in DNA and can be used to monitor cellular proliferation. We have already addressed a number of the problems associated with interpreting the PET images of [C- 11]TdR including the contributions to TdR metabolism of intracellular pools, reutilization., and degradation. To further validate imaging with thymidine we are continuing to study the biochemistry and kinetics of TdR metabolism. In particular this proposal will study the distribution of the major metabolite of thymidine, labeled CO2, and its tissue fixation. This information is being combined into kinetic models. We ire further developing such models to simplify our data analysis scheme and to produce images of DNA synthesis. While thymidine is proving clinically useful, we have begun to search for nucleoside analogs which will monitor cell proliferation and have improved imaging characteristics. We plan to test the hypothesis that two diflourinated analogs of thymidine, 5-fluoro-l-(2'-fluoro-2'deoxy-beta-D-ribofuranosyl)uracil (FFUdR) and 5-fluoro-l-(2'-fluoro-2'-deoxy-beta-Darabinosyl)uracil (FFaraU), will provide increased tumor to blood ratios and undergo little degradation in vivo. Such tracers when labeled with F-18 could greatly simplify imaging of cell growth, by eliminating the need for analyzing metabolites. As an added benefit, these compounds are also taken up and retained in cells infected by viruses. We plan to test the hypotheses that these nucleoside analogs, as well as the [F- 18] -labeled adenosine analog (+/-)9-[(1beta,2alpha,3beta)-2,3-bis(hydroxymethyl)-l-cyclobutyl]adenine (F-cyclobut-A), may be useful in detecting and following the response to viral infections. As a model we have chosen to study cytomegalovirus (CMV) infection in mice, since CMV is a major problem in patients with AIDS and those undergoing organ transplants.
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